Persistent hyperlactatemia after initial resuscitation is particularly difficult to interpret as suggested by the extensive research summarized above. Optimizing systemic blood flow might reverse ongoing hypoperfusion, a potential source of anaerobic lactate generation. Under this perspective, some of the pathogenic factors involved in hyperlactatemia are potentially flow-sensitive, and others are not. Distinction between the two scenarios could strongly impact further resuscitation. If persistent hyperlactatemia is caused by non-hypoperfusion-related mechanisms, then sustained efforts aimed at increasing CO could lead to detrimental effects of excessive fluids or inotropes, a fact now well demonstrated in the literature. The decision of when to consider that a patient has been fully resuscitated and as a consequence stop further interventions is a milestone, and appears as highly relevant since the results of a number of recent studies have increased awareness about the risk of fluid overload and/or of vasopressors and inodilators such as pulmonary edema, increased intraabdominal hypertension, acute kidney injury, delayed weaning, arrhythmias, hepatosplanchnic or myocardial ischemia, among other problems. By these means, over-resuscitation could eventually increase morbidity and/or mortality.